The specific goal of this Phase I STTR is to design, manufacture, characterize and evaluate a set of therapeutic agents that can control the pathogenic CD4+ T cells that mediate an inflammatory autoimmune disease, rheumatoid arthritis (RA). The approach presented is based on patented Recombinant T cell receptor Ligand (RTL) technology (US Patent # 6,270,772) for which Virogenomics holds an exclusive license. The therapeutic efficacy of the RTL technology was first described in experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis. RTLs inhibited activation of pathogenic T cells and reversed clinical score of EAE. The potential of these molecules in the treatment of other human autoimmune diseases provides strong rationale to develop HLA-DR4-derived RTLs for treatment of RA. RA is an inflammatory autoimmune disease in which CD4+ T cells are selectively activated by the presentation of RA susceptible HLA-DR and/or -DQ class II molecules with disease associated antigens, initiating a cascade of inflammatory processes that leads to cartilage destruction and bone erosion at multiple joints. People who have RA will eventually loss work ability and quality of life. This debilitating and chronic disease affects about 1% of general population in the U.S. and around world. In the United States alone this translates to a market size of roughly 2-3 million people. To produce and evaluate HLA-DR4-derived RTLs and prepare these therapeutic agents for commercialization, the following specific aims are proposed:Specific Aim 1: Develop and characterize the recombinant peptide/MHC complexes derived from murine l-Aq and HLA-DR4 alphal and betal domain with or without a covalently linked immunodominant T cell epitope. Specific Aim 2: Evaluate the biological function of the RTLs in DBA1/J mice and humanized HLA-DR4 Transgenic mice